Thioimidazolium Ionic Liquids as Tunable Alkylating Agents

Article abstract of DOI:10.1021/acs.joc.7b02631

Alkylating ionic liquids based on the thioimidazolium structure combine the conventional properties of ionic liquids, including low melting point and nonvolatility, with the alkylating function. Alkyl transfer occurs exclusively from the S-alkyl position, thus allowing for easy derivatization of the structure without compromising specificity. We apply this feature to tune the electrophilicty of the cation to profoundly affect the reactivity of these alkylating ionic liquids, with a caffeine-derived compound possessing the highest reactivity. Anion choice was found to affect reaction rates, with iodide anions assisting in the alkylation reaction through a shuttling process. The ability to tune the properties of the alkylating agent using the toolbox of ionic liquid chemistry highlights the modular nature of these compounds as a platform for alkylating agent design and integration in to future systems.

Full text of DOI:10.1021/acs.joc.7b02631

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Article
Thioimidazolium Ionic Liquids as Tunable Alkylating Agents
Ryan Guterman, Han Miao, and Markus Antonietti
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02631 • Publication Date (Web): 19 Dec 2017
Downloaded from http://pubs.acs.org on December 20, 2017
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Thioimidazolium Ionic Liquids as Tunable
Alkylating Agents
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Ryan Guterman*, Han Miao, Markus Antonietti
Department of Colloid Chemistry, Max Planck Institute of Colloids and Interfaces
Max Planck Institute for Colloids and Interfaces, Am Mühlenberg 1 OTꢀGolm, 14476 Potsdam,
Germany.
ABSTRACT
Alkylating ionic liquids based on the thioimidazolium structure combine the conventional
properties of ionic liquids, including low melting point and nonꢀvolatility, with the alkylating
function. Alkyl transfer occurs exclusively from the Sꢀalkyl position, thus allowing for easy
derivatization of the structure without compromising specificity. We apply this feature to tune
the electrophilicty of the cation to profoundly affect the reactivity of these alkylating ionic
liquids, with a caffeineꢀderived compound possessing the highest reactivity. Anion choice was
found to affect reaction rates, with iodide anions assisting in the alkylation reaction through a
“shuttling” process. The ability to tune the properties of the alkylating agent using the toolbox of
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ionic liquid chemistry highlights the modular nature of these compounds as a platform for
alkylating agent design and integration in to future systems.
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INTRODUCTION
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Ionic liquids (ILs) serve as a platform to design countless chemical structures with a broad
range of chemical, physical, and functional properties. The designer nature of ILs is key to their
implementation for specific functions or applications, including extractions,1 solvents,2–5
polymers,6 electrolytes,7 therapeutics,8 among many more.9 Despite these examples, one
function that has not been introduced is the ability to alkylate, where the IL can selectively
transfer one of its alkyl groups under mild conditions. Such alkylating ionic liquids would
combine the highly useful designer nature of ILs, such as tunable thermal properties,10,11 ionic
conductivity,12,13 and smallꢀmolecule affinity,14,15 with the function of alkylation simultaneously.
This approach could help to interface ILs with alkylation chemistry to address the growing need
for new strategies aimed at producing synthetically challenging, highꢀvalued organic
compounds,16 including aminomethylation, esterification, among others.17–21 For example, the
synthesis of secondary amines from primary still represents a challenge that could benefit from
alkylators that possess defined, yet tunable reactivity.22,23 It would also introduce a new platform
for molecular design and scope to conjugate these molecules to complex systems like
biomolecules, polymers, materials, surfaces, and particles in a simple fashion, a feature not
possible with conventional alkylators yet are common to ionic liquids.24–26 Their nonꢀvolatility
also reduces exposure during handling, allows for their integration in to labꢀonꢀchip devices, and
improve overall safety, which is a consistent problem with many alkylating agents such as MeI,
dimethylsulfate, and methyltriflate.
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To date, some ILs/salts have been used for alkylation reactions.27 In each case however, their
inherent limitations prevent their use as a more general platform for alkylating ionic liquid
design. Common imidazolium salts are too stable and low yielding for such applications and
require microwave irradiation and/or heating above 300 °C,28 or in some cases the addition of a
strong acid.29 Meerwein’s reagent ([Et3O][BF4]) is highly effective for Oꢀ and Nꢀalkylations, but
suffers from moisture sensitivity and poses a significant hazard. Other reactive alkylators such as
oxonium ([OR1R2R3]+), sulfonium [SR1R2R3]+)30, and tetraalkylammonium31 species suffer from
mixed product formation upon alkyl transfer unless all substituents are identical, thus lacking
synthetic and structural versatility. To overcome these limitations, the cation must weakly bind
an alkyl group from one specific position while leaving all others free for derivatization; a
property not yet realized.
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In this context, we introduce the 1,3ꢀdialkylꢀ2ꢀalkylthioimidazolium structure as a platform for
designing a new class of alkylators (Figure 1). Despite their previous discovery and simple
synthesis,32,33 very little is known about their chemical or physical properties. We found that the
key to their utility is the exclusive transfer of the Sꢀalkyl moiety to a variety of different
nucleophiles, leaving all other positions (R2ꢀR5) untouched. This high level of specificity allows
for derivatization at the nitrogen and alkenyl positions independently of its alkylation abilities,
thus acting as a platform for further design. By fineꢀtuning the electrophilicty of the
thioimidazolium cation reactivity can be controlled, with alkylating ionic liquids derived from
simple caffeine capable of alkylating at mild temperature. Surprisingly, the choice of anion had
profound effects on the alkylation process, with iodide anions acting as a methyl “shuttle”, thus
increasing reaction rate. This combination of structural diversity, ease of synthesis, alkyl transfer
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specificity, and tunable reactivity underscores these compounds as a platform for alkylating
agent design.
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Figure 1. 1,3ꢀdialkyꢀ2ꢀthioalkylimidazolium salt as an alkylating agent.
RESULTS AND DISCUSSION
Synthesis of the thioimidazolium salts is described in Scheme S1, which begins with
quaternization of 1ꢀalkylimidazole and subsequent sulfurization to create the 1,3ꢀ
diakylimidazoleꢀ2ꢀthione. Alkylation of the thione with methyliodide proceeds at room
temperature and reintroduces the cationic charge (See SI for procedure). This simplistic and
stepwise synthesis provides a high degree of user control to define the architecture of these
compounds, thus allowing for a chemical library to be easily synthesized. Structures examined
include thioimidazolium cations bearing Nꢀmethyl, benzyl, phenyl, or 2ꢀchlorophenyl groups,
derived from benzimidazole or caffeine, as well as their iodide and
bis(trifluoromethane)sulfonimide (TFSI) salts (Figure 2).34 The labile nature of the thioalkyl
bond was previously described for thiouronium compounds,35 where at elevated temperatures
underwent dealkylation by the nucleophilic attack of the anion. Thermogravimetric analysis
(TGA) of our compounds revealed a similar trend, with mass loss at ~120 °C for iodide salts vs.
~300 °C for TFSI. Complete mass loss was observed at ~300 °C for all iodide salts (Figure S1),
suggesting that the compounds are undergoing dealkylation, followed by volatilization. This
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feature is important as it shows these salts do not evaporate under normal handling condition,
thus limiting exposure and improving safety.
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Figure 2. Chemical structures of thioimidazolium salts examined for their alkylation abilities.
The red methyl group is transferred to the nucleophile.
The susceptibility of these salts to nucleophilic attack by a relatively benign halide suggests that
they may also alkylate other nucleophiles. To assess the role different substitutions and anion has
on the reactivity of these compounds, we examined the reaction kinetics for the methylation of
pyridine; a moderate nucleophile suitable for this study. Upon treatment of 2-I with pyridine
(DMSO at 90 °C, 13 h) and analysis by 1HꢀNMR spectroscopy, we observed the formation of 1ꢀ
methylpyridinium iodide and the appearance of 1,3ꢀdimethylimidazoleꢀ2ꢀthione with no
byproducts and high conversion (86 %; Scheme 1, Figure S2).
Scheme 1. Model for examining alkylating reactivity.
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To confirm that methylation proceeds from the Sꢀalkyl position exclusively, the thione precursor
was methylated with CD3I and then reacted with pyridine (Figure S3). While resonances
consistent with the formation of 1ꢀmethylpyridinium iodide was detected for the aryl hydrogens,
the singlet (NꢀCH3) at 4.41 ppm was not observed, indicating that only CD3 was transferred from
the sulfur position. This finding is significant as it allows for manipulation of the
thioimidazolium structure without compromising its precise alkylation properties. One possible
approach to adjust their alkylating abilities is to control the electrophilicty of the
thioimidazolium cation. It is well known that good electrophiles are also good alkylators, and
that increasing electrophilicity can improves their reactivity. For example, methyltriflate
(MeOTf) violently hydrolyzes in water unlike the more stable methylmesylate (MeOMs),
resulting from the heightened electrophilicity introduced by the trifluoromethyl. To assess this
property for these alkylating agents, the iodide and TFSI salts of compounds 1ꢀ7 were reacted
with one equivalent of pyridine in DMSO and the %converstion to 1ꢀmethylpyridinium
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monitored by HꢀNMR spectroscopy for up to 13 h. Secondꢀorder rate constants were obtained
by plotting 1/[Pyr]t as a function of time and measuring the slope (Table 1, Figure S4 and S5).
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Table 1. Rate constants for reaction of 1ꢀ7 with pyridine.
X = Iodide
X = TFSI
Rate
Rate
Compound*
Constant
(k, M-1min-1);
(kx-I /k2-I)**
Temperature
(°C)
Constant
(k, M-1min-1)
90
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4.7 x 10ꢀ3;0.26
1.8 x 10ꢀ2;1.0
7.0 x 10ꢀ4;0.04
4.0 x 10ꢀ2;2.2
6.9 x 10ꢀ2; 3.8
9.8 x 10ꢀ4;0.05
2.3 x 10ꢀ3;0.13
9.2 x 10ꢀ2;5.1
3.0 x 10ꢀ1;17
No rxn
2.7 x 10ꢀ4
ꢀ
5.0 x 10ꢀ4
5.9 x 10ꢀ4
ꢀ
1
2
3
4
ꢀ
5
6
7
1.6 x 10ꢀ4
4.9 x 10ꢀ4
*A 1:1 molar ratio of compound (0.1851
mmol) and pyridine were combined in DMSOꢀ
d6 (0.400 mL). Rate constants obtained from
pyridine conversions. **k2ꢀI value used for
ratio obtained at 90 °C.
With respect to reactivity, we found that both substitution and anion choice had a significant
effect
on
the
alkylating
abilities
of
these
salts.
Unexpectedly,
the
bis(trifuoromethane)sulfonimide (TFSI) salts possessed significantly lower rate constants (a
factor of ~100 for a given cation structure). This finding indicates that there may be participation
of the anion in the alkylation process. In the presence of KI we found an increase in reaction rate
for 3-TFSI, with greater amounts of iodide further increasing the reaction rate (Figure 3A). The
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reaction rate of 3-TFSI with 1 equivalent of KI was identical to that of 3-I, supporting the
participation of iodide in the alkylation process. Given the high nucleophilicity of iodide, we
believe that at reaction temperature, an equilibrium is established between the thioimidazolium
salt and its thione + MeI (Scheme 2). While this equilibrium was previously described in a
related system,36 this is the first case where it can be used for an alkylation process. Upon
formation of this equilibrium, pyridine irreversibly reacts with MeI, which is then replenished to
continue the reaction. Since iodide is never consumed in the process, it continuously facilitates
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the alkylation by “shuttling” the methyl group, leading to faster kinetics. Both TGAꢀMS and H
NMR spectroscopy experiments confirm that MeI is released upon heating, both neat and in
solution (Figure S6 and S7). The TFSI anion is not sufficiently nucleophilic to dealkylate the
cation and establish such an equilibrium, thus pyridine must attack the thioimidazolium cation
directly, resulting in slower kinetics.
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Figure 3. Conversion plots for the alkylation of pyridine to 1ꢀmethylpyridinium under
various conditions. A) The influence of iodide concentration on the methylation of pyridine
by 3-TFSI (inset shows pristine 3-TFSI). B) Comparing the alkylating power of 1ꢀ7 iodide
salts at either 90 °C (red) or 50 °C (blue). A 1:1 ratio of alkylator and pyridine was used.
Scheme 2. Iodide-assisted alkylation with 3-TFSI
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The reactivity trend with respect to thioimidazolium substitution follows a more predictable
trend, although with even greater differences in reactivity (Table 1 and Figure 3B). Comparing 1ꢀ
I and 2ꢀI, we found that cyclic structures work best for the alkylation process and that aromatic
systems are favourable. Surprisingly, the steric influence of the benzyl and phenyl varieties
appear to be negligible compared to their electron withdrawing properties, with compound 4ꢀI
possessing a rate constant 4x that of 2ꢀI and 20 % higher conversion after 240 min. The presence
of chlorine at the 2ꢀphenyl position in 5ꢀI further increases reactivity and confirms that electron
withdrawing groups increases reactivity. In the case for 6ꢀI and 7ꢀI, extending conjugation at the
alkenyl positions dramatically increased reactivity, allowing for 90 %+ conversion in only a few
hours at 50 °C. In comparison, 1ꢀ3 iodide salts required upwards of 660+ minutes at 90 °C for
similar or slightly less conversions. At 50 °C, the rate constant for 7ꢀI is ~425x larger than 2-I,
illustrating the profound effect chemical structure has on reactivity for these compounds. The
highly electronꢀwithdrawing property of the caffeine structure provided the greatest reactivity
and demonstrates a unique application for this alkaloid as an alkylating ionic liquid precursor.
We assessed the ability of 2ꢀI to alkylate a variety of other substrates to broaden the scope of
these compounds (Table S1). We found that primary, secondary, tertiary amines, and
triphenylphosphine underwent alkylation at low temperatures, while sodium acetate required
elevated temperatures. Diphenylsulfide, acetic acid, water, and alcohols were nonꢀreactive under
tested reaction conditions, however alkaline solutions in either methanol or water quickly
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degraded the cations. The ability to discriminate between functional groups is important and
relies on the reactivity of the alkylator, which we believe will be of interest for future studies.
Further investigations revealed that 2ꢀI is remarkably resistant to hydrolysis, with only ~1ꢀ2 %
decomposition after 24 h in D2O (95 °C) while all other salts could be converted to the TFSI
form in water without decomposition. This demonstrates that the presence of water should not
significantly interfere or hinder the use of these compounds as alkylating agents, or compete with
a nucleophile. We also examined the shelf stability of these compounds and found that after 6
months there were no signs for decomposition. It is possible that dealkylation can only proceed
in solution or at elevated temperatures.
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CONCLUSIONS
In summary, we demonstrate the synthesis and application of alkylating ionic liquids using the
thioimidazolium structure. The synthesis process is simple and uses common reagents, such as
imidazole or naturally occurring caffeine. Alkylation proceeds exclusively from sulfur, providing
the opportunity to manipulate the other positions of the thioimidazolium cation without risk of
mixed product formation. Because of this high degree of specificity, we were able to accelerate
its alkylating kinetics by a factor of ~400 in steps. Introducing electron withdrawing groups at
one nitrogen position increases reactivity by up to 10x, while extending conjugation at the
alkenyl positions increases reactivity by over 400x. Compounds possessing highly conjugated
structures, such as those derived from caffeine and benzimidazole possessed the greatest
reactivity. We also discovered that iodide serves as an activator for the alkylation process by
“shuttling” the methyl group from the thione to the nucleophile, boosting the reaction kinetics by
up to 100x. The reaction can be further tuned depending on the amount of iodide added to the
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system. Finally, we show that this process is general, applies to other nucleophiles, and
represents a convenient platform for alkylating agent design. One challenge that remains is the
use of these alkylating ionic liquids for practical alkylation reactions, which includes purification
of the product from the thione. This can be addressed either by solidꢀsupporting the structures on
a resin or intelligently designing the thione for easy removal. Given the vast utility of both ILs
and alkylating agents, we believe their amalgamation will allow for their integrations in to many
other systems, including, polymers, materials, new synthesis, and therapeutics.
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EXPERIMENTAL
Reagents Caffeine (99 %, anhydrous), 1ꢀphenylimidazole (99 %), 1ꢀ(2ꢀ
chlorophenyl)imidazole (99 %), benzyl chloride (99 %), pyridine (99 %, anhydrous), sulfur
(99.98%), diethylether (≥99 %), methylꢀd3 iodide (99 %), tetramethylthioura (99 %),
benzylamine (99 %), diethylamine (≥99.5 %), triethylamine (≥99 %), benzylalcohol (99.8 %),
methyl acetylacetonate (99 %), 4ꢀaminophenol (≥98 %), diphenylsulfide (≥99%) and potassium
iodide (≥99 %) were purchased from SigmaꢀAldrich and used as received. Deuterated DMSO
was purchased from SigmaꢀAldrich and stored over 4 Å molecular sieves. Methyl iodide (99 %),
1ꢀmethylimidzole (99 %), 1ꢀmethylbenzimidazole (99 %), 1,1,3,3ꢀtetramethylguinidine (99 %),
and triphenylphosphine (99 %) were purchased from Alfa Aesar and used as received. Potassium
carbonate (>99.92 %, anhydrous) was purchased from FisherꢀScientific and used as received.
Methanol (99.9 %), 2ꢀpyrrolidione (99 %), and acetonitrile (99.9 %) were purchased from Merck
and used as received. Lithium bis(trifluoromethane)sulfonylimide (Li TFSI, 99%) was purchased
from IOLITEC and used as received. Ethanolamine (99 %) was purchased from Acros and used
1
as received. Lꢀalanine (99 %) was purchased from Senn chemicals and used as received. H,
19
13C{1H}, and F{1H} NMR spectra were collected on a Bruker DPXꢀ400 spectrometer for the
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characterization of all compounds, while the alkylation kinetic experiments were conducted on a
Varian 600 MR with a OneNMR probe. Spectra were acquired every hour for up to 13 h.
Elemental analysis (EA) was conducted on a VarioMICRO instrument. Thermogravimetric
analysis (TGA) experiments were conducted using a Netzsch TG209ꢀF1 apparatus with a heating
rate of 10 K minꢀ1 under nitrogen flow. TGAꢀMS measurement was performed using a thermo
microbalance TG 209 F1 Libra (Netzsch, Selb, Germany) coupled with a Thermostar Mass
spectrometer (Pfeiffer Vacuum; Asslar/Germany) with a ionization energy of 75eV. An
aluminium crucible was used for the measurement of ~10 mg of sample under a flow of nitrogen
(10ml/min) and a purge flow of 10 ml minꢀ1. The samples were heated at a heat rate of 2.5 K
minꢀ1 to 600 °C in a first measurement with bargraph cyles from m/z 1 to 200 to first observe all
fragments. In a second measurement the found masses were measured in an MID mode with a
heating rate of 0.5 K minꢀ1. Because an exothermal process was detected in the first run and the
TGA thermostate is overcooling the reaction was decelerated. Data was recorded and analyzed
by the Proteus (6.0.0) and Quadstar (7.03, MID modus) software package. Reported
decomposition temperatures were taken at 1% mass loss. Differential scanning calorimetry
(DSC) experiments were performed on a PerkinꢀElmer DSCꢀ1 instrument at a heating/cooling
rate of 10 K minꢀ1 under nitrogen flow and cycled five times. Melting points and glass transitions
were acquired from the final heating cycle. If a melting point could not be observed, it was
determined by visual observation using a Thermo Scientific 9300 melting point apparatus.
Compounds 1-I and 1-TFSI were synthesized according to a literature procedure.21 Mass
spectrometry was conducted on either a HPLC Series 1100 with an ESIꢀSingle Quadropol from
Agilent, or a UPLC Acquity Hꢀclass with ESIꢀQTOF G2ꢀXevoꢀXs from Water. All solvent was
LCꢀMS grade from sigma Aldrich.
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Nucleophile screening procedure
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Compound 2-I (20 mg, 0.074 mmol) was combined with 1 eq. of substrate (see Table S1)
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and DMSOꢀd6 (0.5 mL) in an NMR tube. After 24 h the reaction mixture was analyzed by Hꢀ
NMR spectroscopy to determine whether methylation proceeded. Conversion values were
determined by comparing the integration values of the NꢀCH3 functionality on 2-I (δ = 3.901) to
NꢀCH3 on the 1,3ꢀdimethylimidazolethione byproduct (δ = 3.448) after alkylation. Reactions
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were then heated to 50 °C and then 80 °C at 24 hour intervals, and analyzed by HꢀNMR
spectroscopy prior to increasing temperature. We found that 2-I is stable at these temperatures in
DMSO, so that any decomposition that occurs must be a result of nucleophilic substitution.
Substrates examined include: methanol, acetic acid sodium salt, acetic acid, aniline,
triphenylphosphine,
diphenylsulfide,
1,1,3,3ꢀtetramethylguanidine,
4ꢀaminophenol,
methylacetoacetate, Lꢀalanin, diethylamine, ethanolamine, triethylamine, 2ꢀpyrrolidone,
benzylamine, benzylalcohol.
Kinetics experiment procedure
A 1:1 molar ratio of alkylating agent (compounds 1ꢀ7, both their iodide and TFSI salts)
and pyridine (0.1851 mmol) were dissolved in DMSOꢀd6 (0.4 mL) and added to a standard
NMR tube. The sample was then heated to reaction temperature (50 or 90 °C) and analyzed in-
situ every hour by 1HꢀNMR spectroscopy for up to 13 h. Pyridine conversion was determined by
comparing the integration values of pyridine (δ = 7.99 or 7.35) to 1ꢀmethylpyridinium product
(δ = 8.13), while alkylating agent conversion was determined by comparing the integration
values of the thioimidazolium salt to the thione product. Secondꢀorder rate constants were
obtained by plotting 1/[Pyr]t as a function of time and measuring the slope. In all cases, we found
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the rate of consumption for the alkylator to be equal to the rate of production of 1ꢀ
methylpyridinium (Figure S8).
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Synthesis
1,3-dimethyl-2-(methylthio)-imidazolium iodide (2-I): 1,3ꢀdimethylimidazoleꢀ2ꢀthione19
(1.00 g, 7.80 mmol) was dissolved in acetonitrile (10.0 mL) and methyl iodide (1.661 g, 11.70
mmol) was added dropwise and stirred for 24 h under room temperature. The solution as then
precipitated in diethylether (2x50 mL) and volatiles removed in-vacuo leaving a white powder,
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identified as compound 2ꢀI (1.26 g, 60%) HꢀNMR (400 MHz, DMSOꢀd6): δ = 2.52 (s, 3H),
3.90 (s, 6H), 7.91 (s, 2H). 13C{1H}ꢀNMR (100 MHz, DMSOꢀd6): δ = 17.01 (s), 36.10 (s), 124.66
(s), 140.73 (s). Tdec = 157.3 °C; Tg = not obs; Tm = 161.0 – 163.8 °C. EA calcd. for C6H11IN2S:
C, 26.68; H, 4.10; N, 10.37. Found: C, 26.73; H, 4.07; N, 10.37.
1,3-dimethyl-2-(methylthio)-imidazolium bis(trifluoromethylsulfonyl)imide (2-TFSI):
Compound 2ꢀI (1.00 g, 3.70 mmol) was dissolved in dichloromethane (5.0 mL), followed by the
addition of lithium bis(trifluoromethylsulfonyl)imide (1.277 g, 4.444 mmol) and stirred for 72 h.
The solution was then diluted with dichloromethane (20 mL) and transferred to an extraction
funnel, washed with ultrapure water (3x7.5 mL). The dichloromethane layer was then dried with
a small amount of magnesium sulphate, filtered, and the solvent removed in-vacuo at 60 °C,
leaving a clear, slightly yellow liquid identified as compound 2-TFSI, (0.939 g, 60 %) 1HꢀNMR
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(400 MHz, DMSOꢀd6): δ = 2.51 (s, 3H), 3.90 (s, 6H), 7.88 (s, 2H). C{1H}ꢀNMR (100 MHz,
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DMSOꢀd6): δ = 16.82 (s), 36.01 (s), 119.42 (q, J = 319.5 Hz), 124.71 (s), 140.75 (s). Tdec
=
282.2 °C; Tg = not obs; Tm = 26.6ꢀ26.7 C. EA calcd. for C8H11F6N3O4S3: C, 22.70; H, 2.62; N,
9.93. Found: C, 22.84; H, 2.73; N, 9.96.
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1-benzyl-3-methyl-2-(methylthio)-imidazolium iodide (3-I): 3ꢀmethylꢀ1ꢀbenzylꢀ1,3ꢀ
dihydroimidazoleꢀ2ꢀthione37 (2.00 g, 9.79 mmol) was dissolved in acetonitrile (10.0 mL)
followed by the addition of methyl iodide (2.084 g, 14.69 mmol) dropwise. The mixture was
stirring for 24 h and then precipitated in diethylether (2x50 mL) and volatiles removed in-vacuo
leaving a white powder, identified as compound 3-I (2.20 g, 65 %). 1HꢀNMR (400 MHz, DMSOꢀ
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d6): δ = 2.38 (s, 3H), 3.93 (s, 3H), 5.54 (s, 2H), 7.41 (m, 5H), 7.97ꢀ8.02 (m, 2H). C{1H}ꢀNMR
(100 MHz, DMSOꢀd6): δ = 17.36 (s), 36.20 (s), 52.06 (s), 124.02 (s), 125.55 (s), 127.70 (s),
128.46 (s), 128.90 (s), 134.76 (s), 140.70 (s). Tdec = 120.9 °C; Tg = not obs.; Tm = 123.1ꢀ124.5
°C. EA calcd. for C12H15IN2S: C, 41.63; H, 4.37; N, 8.09. Found: C, 41.32; H, 4.31; N, 8.00.
1-benzyl-3-methyl-2-(methylthio)-imidazolium
bis(trifluoromethylsulfonyl)imide
(3-
TFSI): Compound 3ꢀI (1.00 g, 2.89 mmol) was dissolved in dichloromethane (5.0 mL), followed
by the addition of lithium bis(trifluoromethylsulfonyl)imide (0.995 g, 3.47 mmol) and stirred for
72 h. The solution was then diluted with dichloromethane (20 mL) and transferred to an
extraction funnel, washed with ultrapure water (3x7.5 mL). The dichloromethane layer was then
dried with a small amount of magnesium sulphate, filtered, and the solvent removed in-vacuo at
60 °C, leaving a clear, slightly yellow liquid identified as compound 3-TFSI, (0.937 g, 65 %)
1HꢀNMR (400 MHz, DMSOꢀd6): δ = 2.38 (s, 3H), 3.94 (s, 3H), 5.55 (s, 2H), 7.41 (m, 5H), 7.96ꢀ
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8.01 (m, 2H). C{1H}ꢀNMR (100 M, DMSOꢀd6): δ = 17.22 (s), 36.11 (s), 52.11 (s), 119.44 (q,
1J = 319.8 Hz), 124.04 (s), 125.57 (s), 127.69 (s), 128.46 (s), 128.88 (s), 134.72 (s), 140.71 (s).
Tdec = 282.4 °C; Tg = ꢀ50.5 °C; Tm = not obs. EA calcd. for C14H15F6N3O4S3: C, 33.67; H, 3.03;
N, 8.41. Found: C, 33.71; H, 2.98; N, 8.38.
1-phenyl-3-methyl-2-(methylthio)-imidazolium iodide (4-I): 1ꢀmethylꢀ3ꢀphenylimidazoleꢀ
2ꢀthione19 (0.439 g, 2.27 mmol) was dissolved in acetonitrile (5 mL) followed by the addition of
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methyliodide (0.484 g, 3.41 mmol). The solution was stirred for 24 h and then precipitated in
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diethylether (50 mL). The solution was decanted and volatiles removed in-vacuo leaving a white
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powder identified as 4-I (0.609 g, 80%). HꢀNMR (400 MHz, DMSOꢀd6): δ = 2.34 (s, 3H, Sꢀ
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CH3), 4.00 (s, 3H), 7.67 (m, 5H), 8.12ꢀ8.18 (m, 2H). CꢀNMR (100 MHz, DMSOꢀd6): δ = 17.2
(s), 36.3 (s), 125.0 (s), 125.1 (s), 126.3 (s), 129.7 (s), 130.5 (s), 135.3 (s), 141.8 (s). Tdec = 138.1
°C; Tg = 87.3 °C; Tm =not obs. EA calcd. for C11H13IN2S: C, 39.77; H. 3.94; N, 8.43. Found: C,
39.89; H. 3.63; N, 8.49.
1-phenyl-3-methyl-2-(methylthio)-imidazolium bis(trifluoromethylsulfonyl)imide (4-
TFSI): Compound 4-I (0.347 g, 1.04 mmol) was dissolved in deionized water (5 mL) followed
by the addition of LiTFSI (0.315 g, 1.10 mmol) in deionized water (3 mL). The mixture was
stirred for 24 h and then decanted. The residue was then rinsed with fresh deionized water (3x5
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mL) and volatiles removed in-vacuo resulting in a clear viscous oil identified as 4-TFSI. Hꢀ
NMR (400 MHz, DMSOꢀd6): δ = 2.33 (s, 3H, SꢀCH3), 4.00 (s, 3H), 7.67 (m, 5H), 8.12ꢀ8.18 (m,
2H). 13CꢀNMR (100 MHz, DMSOꢀd6): δ = 17.2 (s), 36.3 (s), 125.0 (s), 125.1 (s), 126.3 (s),
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129.7 (s), 130.5 (s), 135.3 (s), 141.8 (s). CꢀNMR (100 MHz, DMSOꢀd6): δ = 17.1 (s), 36.3 (s),
119.4 (q, 1JCꢀF = 320 Hz), 125.1 (s), 125.2 (s), 126.3 (s), 129.7 (s), 130.6 (s), 135.3 (s), 141.8 (s).
Tdec = 290.7 °C; Tg = not obs; Tm = 112.0 °C. MS (ESI+) m/z: [M]+ Calcd for [C11H13N2S]+
205.08; Found 205.10 ([cation]+, 100).
1-(2-chlorophenyl)-3-methylimidazolium iodide (R1-5): 1ꢀ(2ꢀchlorophenyl)imidazole
(1.00 g, 5.60 mmol) was dissolved in acetonitrile (10 mL) and methyl iodide (1.59 g, 11.20
mmol) added dropwise. The solution was stirred for 24 h and volatiles removed in-vacuo leaving
a slightly yellow powder identified as 1ꢀ(2ꢀchlorophenyl)ꢀ3ꢀmethylimidazolium iodide (1.79 g,
99%). 1HꢀNMR (400 MHz, DMSOꢀd6): δ = 3.98 (s, 3H), 7.67 (m, 2H), 7.76ꢀ7.84 (m, 4H), 7.98
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(s, 1H), 8.12 (s, 1H), 9.58 (s, 1H). CꢀNMR (100 MHz, DMSOꢀd6): δ = 36.2 (s), 123.8 (s),
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123.9 (s), 128.6 (s), 128.7 (s), 128.8 (s), 130.6 (s), 132.3 (s), 132.4 (s), 138.0 (s). Tdec = 220 °C;
Tg = not obs.; Tm = 124.4ꢀ130.0 °C. EA calcd. for C10H10ClN2I: C, 37.47; H. 3.14; N, 8.74.
Found: C, 37.57; H. 3.26; N, 8.76.
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1-(2-chlorophenyl)-3-methylimidazole-2-thione
(R2-5)
:1ꢀ(2ꢀchlorophenyl)ꢀ3ꢀ
methylimidazolium iodide (2.59 g, 8.08 mmol) was dissolved in methanol (50 mL) followed by
the addition of sulfur (0.412 g, 12.12 mmol) and stirred for 10 minutes. Potassium carbonate
(1.45 g, 10.5 mmol) was then added and the mixture stirred for 24 h. Methanol was then fully
evaporated in-vacuo and the residue rinsed with water (3x50 mL), recrystallized from
isopropanol, and dried in-vacuo to leaving yellow crystals identified as 1ꢀ(2ꢀchlorophenyl)ꢀ3ꢀ
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methylimidazoleꢀ2ꢀthione (0.724 g, 40%). HꢀNMR (400 MHz, DMSOꢀd6): δ = 3.54 (s, 3H),
7.24ꢀ7.33 (m, 2H), 7.49 (m, 3H), 7.66ꢀ7.68 (m, 1H). 13CꢀNMR (100 MHz, DMSOꢀd6): δ = 34.6
(s), 118.2 (s), 119.3 (s), 127.9 (s), 130.0 (s), 130.6 (s), 130.62 (s), 131.2 (s), 135.7 (s), 163.2 (s).
Tm = 111ꢀ112 °C. HRMS (ESI+/TOF) m/z: [M]+ Calcd for C10H9ClN2S 224.01750; Found
224.0143.
1-(2-chlorophenyl)-3-methyl-2-(methylthio)-imidazolium
iodide
(5-I):
1ꢀ(2ꢀ
chlorophenyl)ꢀ3ꢀmethylimidazoleꢀ2ꢀthione (0.512 g, 2.28 mmol) was dissolved in acetonitrile
(30 mL) and methyl iodide (0.647 g, 4.56 mmol) added dropwise. The solution was stirred for 24
h and volatiles removed in-vacuo leaving a slightly yellow powder identified as 5-I (0.836 g,
99%). 1HꢀNMR (400 MHz, DMSOꢀd6): δ = 2.40 (s, 3H, SꢀCH3), 4.00 (s, 3H), 7.67ꢀ7.87 (m,
4H), 8.21ꢀ8.23 (m, 2H). 13CꢀNMR (100 MHz, DMSOꢀd6): δ = 17.2 (s), 36.6 (s), 125.4 (s), 125.8
(s), 128.7 (s), 129.8 (s), 130.1 (s), 130.4 (s), 132.6 (s), 132.9 (s), 142.5 (s). Tdec = 112.1 °C; Tg =
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not obs; Tm = 112 °C. EA calcd. for C11H12ClN2S: C, 36.04; H. 3.30; N, 7.64. Found: C, 35.55;
H. 3.10; N, 7.46.
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1,3-dimethyl-2-(methylthio)-benzoimidazolium iodide (6-I): 1,3ꢀdimethylbenzimidazoleꢀ
2ꢀthione38 (1.15 g, 6.39 mmol) was added to acetonitrile (30 mL) and stirred for 10 minutes
before adding methyl iodide (1.36 g 9.59 mmol). The solution was stirred for 24 h, concentrated
by rotary evaporation, and precipitated in diethylether (100 mL). The solution was then decanted
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and volatiles removed in-vacuo, leaving a white powder identified as 6-I (0.83 g, 41 %). Hꢀ
NMR (400 MHz, DMSOꢀd6): δ = 2.72 (s, 3H, SꢀCH3), 4.13 (s, 6H), 7.72 (m, 2H), 8.06 (m, 2H).
13CꢀNMR (100 MHz, DMSOꢀd6): δ = 17.1 (s), 33.2 (s), 113.2 (s), 126.7 (s), 132.1 (s), 149.9 (s).
Tdec = 114.8 °C; Tg = 88.5 °C; Tm = 108.0ꢀ108.2 °C. EA calcd. for C10H13IN2S: C, 37.51; H.
4.09; N, 8.75. Found: C, 38.11; H. 3.83; N, 8.84.
1,3-dimethyl-2-(methylthio)-benzoimidazolium bis(trifluoromethylsulfonyl)imide (6-
TFSI): Compound 6-I (0.950 g, 2.967 mmol) was dissolved in deionized water (10 mL)
followed by the dropwise addition of LiTFSI (0.894 g, 3.115 mmol) in deionized water (5 mL).
The solution was stirred for 24 h and the precipitate rinsed with deionized water (3x5 mL) and
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dried in-vacuo to isolate a white powder identified as 6-TFSI (0.883 g, 65%). HꢀNMR (400
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MHz, DMSOꢀd6): δ = 2.71 (s, 3H, SꢀCH3), 4.13 (s, 6H), 7.72 (m, 2H), 8.07 (m, 2H). FꢀNMR
(376 MHz, DMSOꢀd6): δ = ꢀ78.8 (s) 13CꢀNMR (100 MHz, DMSOꢀd6): δ = 17.0 (s), 33.1 (s),
113.2 (s), 119.4 (q, 1JCꢀF = 320 Hz), 126.8 (s), 132.1 (s), 149.9 (s). Tdec = 265.9 °C; Tg = 13.9 °C;
Tm = 120 °C. EA calcd. for C12H13F6N3O4S3: C, 30.44; H. 2.77; N, 8.88. Found: C, 30.72; H.
2.72; N, 8.90.
1,3,7,9-tetramethyl-8-thioxo-3,7,8,9-tetrahydropurine-2,6-dione (RS7): Compound RS7
was prepared according to a modified literature procedure.39 Compound R7 (3.86 g, 11.5 mmol)
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was dissolved in methanol (175 mL), followed by the addition of sulfur (0.44 g, 13.8 mmol), and
potassium carbonate (3.18 g, 23.0 mmol). The mixture was stirred for 48 h and volatiles removed
by rotary evaporation. The residue was rinsed with deionized water (3x50 mL) and recrystallized
from isopropanol, and volatiles removed in-vacuo leaving a white crystals identified as RS7
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(1.11 g, 40 %). HꢀNMR (400 MHz, DMSOꢀd6): δ = 3.23 (s, 3H), 3.71 (s, 3H), 3.79 (s, 3H),
3.79 (s, 3H), 3.96 (s, 3H). Tm = 267.4ꢀ269.3 °C.
1,3,7,9-tetramethyl-8-(methylthio)-2,6-dioxo-2,3,6,9-tetrahydropurinium iodide (7-I):
Compound RS7 (1.03 g, 4.16 mmol) was combined with methyl iodide (6.20 g, 41.6 mmol) in
acetonitrile (20 mL) and stirred for 7 days at room temperature. Volatiles were then removed in-
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vacuo leaving a yellow powder identified as compound 7-I (1.64 g, 99%). HꢀNMR (400 MHz,
DMSOꢀd6): δ = 2.59 (s, 3H, SꢀCH3), 3.29 (s, 3H), 3.79 (s, 3H), 4.19 (s, 3H), 4.23 (s, 3H). 13Cꢀ
NMR (100 MHz, DMSOꢀd6): δ = 17.6 (s), 28.5 (s), 32.1 (s), 35.7 (s), 36.3 (s), 108.6 (s), 140.0
(s), 145.8 (s), 150.00 (s), 152.90 (s). Tdec = 126.8 °C; Tg = not obs; Tm =not obs. EA calcd. for
C10H15IN4O2S: C, 31.42; H. 3.96; N, 14.66. Found: C, 31.80; H. 3.72; N, 14.69.
1,3,7,9-tetramethyl-8-(methylthio)-2,6-dioxo-2,3,6,9-tetrahydropurinium
bis(trifluoromethylsulfonyl)imide (7-TFSI): Compound 7-I (1.55 g, 4.07 mmol) was dissolved in
deionized water (50 mL) and combined with an aqueous solution (10 mL) of LiTFSI (1.23 g,
4.27 mmol), resulting in the formation of a precipitate. After stirring for 24 h, the precipitate was
rinsed with water (3x10 mL) and volatiles removed in-vacuo, leaving a white powder identified
as 7-TFSI (1.31 g, 60%). 1HꢀNMR (400 MHz, DMSOꢀd6): δ = 2.59 (s, 3H, SꢀCH3), 3.29 (s, 3H),
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3.79 (s, 3H), 4.19 (s, 3H), 4.23 (s, 3H). CꢀNMR (100 MHz, DMSOꢀd6): δ = 17.5 (s), 28.5 (s),
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32.1 (s), 35.6 (s), 36.3 (s), 108.6 (s), 119.4 (q, JCꢀF = 320 Hz) 140.0 (s), 145.8 (s), 150.0 (s),
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152.9 (s). Tdec = 269.1 °C; Tg = 75 °C; Tm = 143 °C. EA calcd. for C12H15F6N5O6S3: C, 26.92; H.
2.82; N, 13.08. Found: C, 27.13; H. 2.72; N, 13.03.
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AUTHOR INFORMATION
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Corresponding Author
*Eꢀmail: ryan.guterman@mpikg.mpg.de
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript. ‡These authors contributed equally.
ACKNOWLEDGMENT
The authors would like to thank Dr. Kerry Gilmore for his helpful discussions and Antje
Voelkel for her assistance with the TGAꢀMS. We thank the European Research Council (ERC)
and the Max Planck Institute (MPI) for their funding.
Supporting information. The synthetic scheme, TGA thermographs, NMR experiments, and
kinetic data.
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